The response of intrinsic brain cells to virus infection in the central nervous system (CNS) can influence virus infection in the brain and the clinical outcome of disease. Our studies have focused on two animal models of virus-mediated neuropathogenesis to determine the host response proteins that regulate disease induction. We have identified several host response proteins that are upregulated in the CNS following neurovirulent retrovirus infection or bunyavirus infection and may influence neuronal damage. In FY11, we identified multiple proteins that influenced disease pathogenesis but primarily focused on one particular protein whose expression strongly correlated with retroviral neuropathogensis, neuropeptide Y (NPY). We found that NPY was produced by neurons at the late stages of virus infection in the CNS. Using knockout mice, we found that NPY plays a protective role during retrovirus infection and that mice deficient in NPY developed clinical disease at a much faster rate than wildtype mice. We have identified two specific pathways by which neuropeptide Y influences retroviral neuropathogenesis and are currently examining the mechanisms of NPY protection during retroviral pathogenesis in the CNS.